The long-term goal of Dr. Jingbo Pi is to become a successful independent investigator in the research field of diabetes. The large majority of Dr. Pi's time will be spent on the research project that he has described in his proposal on reactive oxygen species and (-cell function (summarized below in the Project Summary). This experience will provide him with both the theoretical and practical knowledge base upon which to build a career as an independent investigator in this area. The major immediate goals in his career development plan are (i) enrichment of his knowledge and research experience in the field of diabetes;(ii) develop excellence in scientific presentation, both oral and written;and (iii) grantsmanship and how to best organize the necessary resources and collaborators to successfully pursue future independent studies. Project Summary: Impaired metabolic signal transduction that mediates insulin secretion is fundamental in the pathophysiology of diabetes. Identification of valid targets for intervention in the treatment of diabetes requires knowledge of the metabolic signals that lead to stimulation of insulin secretion as well as its failure. This grant focuses on the roles of reactive oxygen species (ROS) as putative signals mediating glucose-stimulated insulin secretion (GSIS). There are two specific aims: (i) Test the hypothesis that ROS, in the low physiological range, are additional metabolic signals that regulate a cytosolic redox network to modulate insulin secretion;(ii) Test the hypothesis that antioxidant response mediated by transcription factor Nrf2 enhances cellular ROS scavenging activity and thus negatively regulates GSIS. The unique features of pancreatic (-cells, with relatively low expression and activity of many of antioxidant enzymes, provide a sensitive system for ROS/redox signaling. Importantly, the generation of ROS, which have emerged as physiological mediators of many cellular responses, is coupled to oxidative mitochondrial metabolism. We propose to (i) investigate the modulatory effect of glucose on intracellular ROS/redox signaling and the correlation with GSIS in INS-1 (832/13) cells and isolated intact mouse islets;(ii) evaluate the stimulation effects of ROS on insulin secretion and the inhibition effect of antioxidants on GSIS in these models;(iii) examine the effects of targeted gene disruption of Nrf2 or UCP2 on ROS/redox signaling and GSIS. Nrf2 is a central regulator in both constitutive and inducible gene expression of antioxidant enzymes, whereas UCP2 has been recognized as a negative regulator of mitochondria-derived ROS. Relevance: This project will help to foster the development of a successful scientist specializing in diabetes research. His currently proposed and future studies will contribute new insights into the mechanisms of diabetes and hopefully advance preventive measures and treatment strategies for this disease.